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As there is no effective treatment for all types of AMD, identifying modifiable risk factors is of great importance. This review evaluates the epidemiological evidence associating smoking with AMD. Systematic review of published epidemiological studies evaluated against established criteria for evidence of a causal relationship. In total, 17 studies (cross-sectional studies, prospective cohort studies, and case–control studies) were included in the review. A total of 13 studies found a statistically significant association between smoking and AMD with increased risk of AMD of two- to three-fold in current-smokers compared with never-smokers. Five studies found no association between smoking and AMD. There was also evidence of dose-response, a temporal relationship and reversibility of effect. The literature review confirmed a strong association between current smoking and AMD, which fulfilled established causality criteria. Cigarette smoking is likely to have toxic effects on the retina. 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data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Review</li> <li class="c-article-identifiers__item">Published: <time datetime="2005-09-06">06 September 2005</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Smoking and age-related macular degeneration: a review of association</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-J-Thornton-Aff1" data-author-popup="auth-J-Thornton-Aff1" data-author-search="Thornton, J">J Thornton</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-R-Edwards-Aff1" 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data-track="click" data-track-action="open author" data-track-label="link" href="#auth-I-Buchan-Aff1" data-author-popup="auth-I-Buchan-Aff1" data-author-search="Buchan, I">I Buchan</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 6 authors for this article" title="Show all 6 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-S_P-Kelly-Aff4" data-author-popup="auth-S_P-Kelly-Aff4" data-author-search="Kelly, S P" data-corresp-id="c1">S P Kelly<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff4">4</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" 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data-test="access-count"> <p class="c-article-metrics-bar__count">16k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">401 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">74 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/6701978/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Purpose</h3><p>Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss in the Western world. As there is no effective treatment for all types of AMD, identifying modifiable risk factors is of great importance. This review evaluates the epidemiological evidence associating smoking with AMD.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Methods</h3><p>Systematic review of published epidemiological studies evaluated against established criteria for evidence of a causal relationship.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Results</h3><p>In total, 17 studies (cross-sectional studies, prospective cohort studies, and case–control studies) were included in the review. A total of 13 studies found a statistically significant association between smoking and AMD with increased risk of AMD of two- to three-fold in current-smokers compared with never-smokers. Five studies found no association between smoking and AMD. There was also evidence of dose-response, a temporal relationship and reversibility of effect.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Conclusion</h3><p>The literature review confirmed a strong association between current smoking and AMD, which fulfilled established causality criteria. Cigarette smoking is likely to have toxic effects on the retina. In spite of the strength of this evidence, there appears to be a lack of awareness about the risks of developing eye disease from smoking among both healthcare professionals and the general public.</p></div></div></section> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41433-023-02481-4/MediaObjects/41433_2023_2481_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41433-023-02481-4?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1038/s41433-023-02481-4">Frequency of coexistent eye diseases and cognitive impairment or dementia: a systematic review and meta-analysis </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">15 March 2023</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41598-024-65813-8/MediaObjects/41598_2024_65813_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41598-024-65813-8?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1038/s41598-024-65813-8">Association of smoking cessation patterns and untreated smoking with glaucoma, cataract, and macular degeneration: a population-based retrospective study </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">26 June 2024</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41598-020-79865-z/MediaObjects/41598_2020_79865_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41598-020-79865-z?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41598-020-79865-z">Smoking, urinary cotinine levels and incidence of visual impairment </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">11 January 2021</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1740562555, embedded_user: 'null' } }); </script> <div class="main-content"> <section data-title="Introduction"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction</h2><div class="c-article-section__content" id="Sec1-content"><p>Early signs of age-related maculopathy (ARM) are common in the elderly eye and age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss in the developed world. The prevalence of neovascular AMD and/or geographic atrophy in the US population aged ≥40 years is estimated to be 1.47%, with 1.75 million citizens having AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564–572." href="/articles/6701978#ref-CR1" id="ref-link-section-d106275198e484">1</a></sup> In the UK, AMD is the most common cause of blindness registration.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Evans J, Rooney C, Ashwood F, Dattani N, Wormald R . Blindness and partial sight in England and Wales: April 1990–March 1991. Health Trends 1996; 28: 5–12." href="/articles/6701978#ref-CR2" id="ref-link-section-d106275198e488">2</a></sup> Owen at al,<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Owen CG, Fletcher AE, Donoghue AR, Rudnicka AR . How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom? Br J Ophthalmol 2003; 87: 312–317." href="/articles/6701978#ref-CR3" id="ref-link-section-d106275198e492">3</a></sup> estimated that 214 000 people in the UK may have visual impairment caused by AMD.</p><p>Recent therapeutic developments for AMD have concentrated on high-technology interventions such as photodynamic therapy (PDT), macular rotational surgery, and radiotherapy, with new therapies such as intravitreal antivascular endothelial growth factor (VEGF) administration currently undergoing evaluation or registration. These costly treatments provide only partial clinical benefit to selected patients; at best they slow progression of disease and cannot restore vision. Therefore, attention is focusing on identification of modifiable risk factors for AMD.</p><p>Age is the most important, but clearly nonmodifiable, risk factor for AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Evans JR . Risk factors for age-related macular degeneration. Prog Retin Eye Res 2001; 20: 227–253." href="/articles/6701978#ref-CR4" id="ref-link-section-d106275198e502">4</a></sup> Genetic susceptibility, as indicated by a positive family history of AMD, is associated with a high risk of the disease.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Evans JR . Risk factors for age-related macular degeneration. Prog Retin Eye Res 2001; 20: 227–253." href="/articles/6701978#ref-CR4" id="ref-link-section-d106275198e506">4</a></sup> While progress is being made on consolidating the chromosomal locations of several AMD susceptibility loci, the role of genetic factors in AMD is likely to result from the combined effects exerted by multiple gene variants interacting with environmental factors.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, Branham KE . Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am J Hum Genet 2004; 74: 482–494." href="/articles/6701978#ref-CR5" id="ref-link-section-d106275198e510">5</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Tuo J, Bojanowski CM, Chan CC . Genetic factors of age-related macular degeneration. Prog Retin Eye Res 2004; 23: 229–249." href="/articles/6701978#ref-CR6" id="ref-link-section-d106275198e513">6</a></sup> Considering modifiable risk factors, low dietary intake or low plasma concentrations of antioxidants may be associated with AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Evans JR . Risk factors for age-related macular degeneration. Prog Retin Eye Res 2001; 20: 227–253." href="/articles/6701978#ref-CR4" id="ref-link-section-d106275198e517">4</a></sup> Dietary and micronutrient supplementation is increasingly considered as preventive intervention although the protective effect of direct vitamin interventions remains uncertain.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Evans JR . Antioxidant Vitamin and Mineral Supplements for Age-related Macular Degeneration (Cochrane Review). Update Software: Oxford, 2003." href="/articles/6701978#ref-CR7" id="ref-link-section-d106275198e521">7</a></sup> Cardiovascular disease and AMD may share a common risk factor profile, for example, obesity, dietary fat, alcohol consumption, and smoking.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Evans JR . Risk factors for age-related macular degeneration. Prog Retin Eye Res 2001; 20: 227–253." href="/articles/6701978#ref-CR4" id="ref-link-section-d106275198e526">4</a></sup> Dietary fat may also be a risk factor independent of its relation to cardiovascular disease, with both animal and vegetable fats implicated.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Seddon JM, Rosner B, Sperduto PD, Yannuzzi L, Haller JA, Blair NP . Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol 2001; 119: 1191–1199." href="/articles/6701978#ref-CR8" id="ref-link-section-d106275198e530">8</a></sup></p><p>Smoking is a major risk factor for many chronic diseases, especially respiratory and cardiovascular disease.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Scientific Committee on Tobacco And Health. Report of the Scientific Committee on Tobacco and Health. The Stationary Office: London, 1998." href="/articles/6701978#ref-CR9" id="ref-link-section-d106275198e536">9</a></sup> The effects of smoking on the eye are not well recognised. This paper evaluates the evidence for a causal association between smoking and AMD.</p></div></div></section><section data-title="Methods"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Methods</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">Searching and review of studies</h3><p>MEDLINE (1966 to July 2003) and EMBASE (1980 to July 2003) were searched using combinations of the key words of ‘smoking’, ‘macular degeneration’, and ‘age-related maculopathy’. Bibliographies were checked for further relevant studies.</p><p>Studies were included if they were epidemiological studies (case–control, cohort or cross-sectional studies) published in English, assessed the relationship between tobacco smoking and AMD or ARM, and included an estimate of the degree of association (odds ratio (OR) or relative risk (RR)). The outcome measure was the presence of ARM or AMD as defined by the investigators of each study. The evidence was reviewed against a framework for assessing the evidence for causality derived from Hill<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Hill AB . The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295–300." href="/articles/6701978#ref-CR10" id="ref-link-section-d106275198e555">10</a></sup> and subsequently modified by Susser<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Susser M . What is a cause and how do we know one? A grammar for pragmatic epidemiology. Am J Epidemiol 1991; 133: 635–647." href="/articles/6701978#ref-CR11" id="ref-link-section-d106275198e559">11</a></sup> (see box).</p> <div style="width:300px; max-width:100%;" class="c-article-section__illustration-center c-article-section__illustration u-clearfix" data-test="illustration" id="i1"><div class="c-article-section__figure c-article-section__figure--1-border"><picture><source type="image/webp" srcset="//media.springernature.com/w300/springer-static/image/art%3A10.1038%2Fsj.eye.6701978/MediaObjects/41433_2005_Article_BF6701978_Figa_HTML.gif?as=webp"><img class="c-article-section__figure--1-border-image" alt="" width="300" src="//media.springernature.com/w300/springer-static/image/art%3A10.1038%2Fsj.eye.6701978/MediaObjects/41433_2005_Article_BF6701978_Figa_HTML.gif"></picture></div></div></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec4-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec4">Results</h2><div class="c-article-section__content" id="Sec4-content"><h3 class="c-article__sub-heading" id="Sec5">Design of studies</h3><p>In total, 23 studies examined the link between smoking and AMD. Two studies were excluded from the review as they were not published in the English language.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Shiraga F, Matsuo N, Katayama S, Inoue Y, Tsuji T, Mihara M . Neovascular age-related macular degeneration: a case–control study. Folia Ophthalmol Jpn 1987; 38: 525–533." href="/articles/6701978#ref-CR12" id="ref-link-section-d106275198e587">12</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Starzycka M, Slomska J, Gorniak-Bednarz A, Ortyl E . Risk factors for age-related macular degeneration. Klinika Oczna 1997; 99: 249–251." href="/articles/6701978#ref-CR13" id="ref-link-section-d106275198e590">13</a></sup> One study was excluded because it was a case series.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Paetkau ME, Boyd TA, Grace M, Bach-Mills J, Winship B . Senile disciform macular degeneration and smoking. Can J Ophthalmol 1978; 13: 67–71." href="/articles/6701978#ref-CR14" id="ref-link-section-d106275198e594">14</a></sup> Three studies did not report an OR or RR.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Pauleikhoff D, Wormald RP, Wright L, Wessing A, Bird AC . Macular disease in an elderly population. Ger J Ophthalmol 1992; 1: 12–15." href="/articles/6701978#ref-CR15" id="ref-link-section-d106275198e598">15</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Hirvela H, Luukinen H, Laara E, Sc L, Laatikainen L . Risk factors of age-related maculopathy in a population 70 years of age or older. Ophthalmology 1996; 103: 871–877." href="/articles/6701978#ref-CR16" id="ref-link-section-d106275198e601">16</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Maltzman B, Mulvihill M, Greenbaum A . Senile macular degeneration and risk factors: a case–control study. Ann Ophthamol 1979; 11: 1197–1201." href="/articles/6701978#ref-CR17" id="ref-link-section-d106275198e604">17</a></sup> We attempted to calculate crude ORs for these studies using the available data. Pauleikhoff <i>et al</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Pauleikhoff D, Wormald RP, Wright L, Wessing A, Bird AC . Macular disease in an elderly population. Ger J Ophthalmol 1992; 1: 12–15." href="/articles/6701978#ref-CR15" id="ref-link-section-d106275198e610">15</a></sup> did not contain sufficient data to allow calculation of an OR. In the study by Hirvela <i>et al</i>,<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Hirvela H, Luukinen H, Laara E, Sc L, Laatikainen L . Risk factors of age-related maculopathy in a population 70 years of age or older. Ophthalmology 1996; 103: 871–877." href="/articles/6701978#ref-CR16" id="ref-link-section-d106275198e618">16</a></sup> there were very large differences in smoking between men and women but there were insufficient data to calculate a sex-specific OR. However, the authors reported there was no association between smoking and AMD in a stepwise logistic regression analysis. The fourth study was a very small (30 cases) individually matched case–control study. A valid OR (allowing for matching) could not be calculated as this would have required access to the raw data.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Maltzman B, Mulvihill M, Greenbaum A . Senile macular degeneration and risk factors: a case–control study. Ann Ophthamol 1979; 11: 1197–1201." href="/articles/6701978#ref-CR17" id="ref-link-section-d106275198e622">17</a></sup> Thus, 17 studies were included in the review.</p><p>Study designs were cross-sectional (seven studies—<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/6701978#Tab1">Table 1</a>), prospective cohort (four studies, including one study which reported results from two time points—<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/6701978#Tab2">Table 2</a>), and case–control (six studies—<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/6701978#Tab3">Table 3</a>).</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 Cross-sectional studies examining the association between smoking and AMD: current-smokers <i>vs</i> never-smokers (unless stated otherwise)</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/6701978/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-2"><figure><figcaption class="c-article-table__figcaption"><b id="Tab2" data-test="table-caption">Table 2 Prospective cohort studies examining the association between smoking and AMD: current-smokers <i>vs</i> never-smokers (unless otherwise stated)</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/6701978/tables/2" aria-label="Full size table 2"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-3"><figure><figcaption class="c-article-table__figcaption"><b id="Tab3" data-test="table-caption">Table 3 Case–control studies examining the association between smoking and AMD: current-smokers <i>vs</i> never-smokers (unless otherwise stated)</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/6701978/tables/3" aria-label="Full size table 3"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Most studies originated from North America (eight studies), Europe (five studies) or Australia (two studies). For the cross-sectional and prospective cohort studies, subjects were recruited from the general population or through selected occupations such as watermen,<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989; 107: 875–879." href="/articles/6701978#ref-CR18" id="ref-link-section-d106275198e2320">18</a></sup> physicians<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2324">19</a></sup> and nurses.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e2328">20</a></sup> For the case–control studies, cases were recruited through eye clinics, and hospital controls were recruited through eye clinics<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Hyman LG, Lilienfeld AM, Ferris III FL, Fine SL . Senile macular degeneration: a case–control study. Am J Epidemiol 1983; 118: 213–227." href="/articles/6701978#ref-CR21" id="ref-link-section-d106275198e2332">21</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Eye Disease Case-Control Study Group. Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol 1992; 110: 1701–1708." href="/articles/6701978#ref-CR22" id="ref-link-section-d106275198e2335">22</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D et al. Case–control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol 1998; 82: 996–1002." href="/articles/6701978#ref-CR23" id="ref-link-section-d106275198e2338">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Age-related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case–control study in the age-related eye disease study: AREDS Report Number 3. Ophthalmology 2000; 107: 2224–2232." href="/articles/6701978#ref-CR24" id="ref-link-section-d106275198e2341">24</a></sup> or general medicine clinics.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y . Smoking and neovascular form of age related macular degeneration in late middle aged males: findings from a case–control study in Japan. Research Committee on Chorioretinal Degenerations. Br J Ophthalmol 1997; 81: 901–904." href="/articles/6701978#ref-CR25" id="ref-link-section-d106275198e2345">25</a></sup></p><p>The age range for subjects in most studies was 40–80 years. The sex of subjects was not always reported, but approximately equal numbers of males and females were included in studies where data were available. Some studies recruited only males<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989; 107: 875–879." href="/articles/6701978#ref-CR18" id="ref-link-section-d106275198e2351">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2354">19</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y . Smoking and neovascular form of age related macular degeneration in late middle aged males: findings from a case–control study in Japan. Research Committee on Chorioretinal Degenerations. Br J Ophthalmol 1997; 81: 901–904." href="/articles/6701978#ref-CR25" id="ref-link-section-d106275198e2357">25</a></sup> or females.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e2361">20</a></sup></p><p>We also reviewed two pooled analyses of the findings of three large cross-sectional studies<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001; 108: 697–704." href="/articles/6701978#ref-CR26" id="ref-link-section-d106275198e2368">26</a></sup> and their subsequent extension into cohort studies.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Tomany SC, Wang JJ, van Leeuwen R, Klein R, Mitchell P, Vingerling JR et al. Risk factors for incident age-related macular degeneration. Pooled findings from 3 continents. Ophthalmology 2004; 111: 1280–1287." href="/articles/6701978#ref-CR27" id="ref-link-section-d106275198e2372">27</a></sup></p><h3 class="c-article__sub-heading" id="Sec6">Association between smoking and AMD</h3><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec7">What is the strength and consistency of the association?</h4><p>Of seventeen included studies, 13 found a statistically significant association between smoking and one or more types of AMD, with increased risks for current-smokers or ever-smokers compared with non-smokers or never-smokers (RR/OR 1.06–4.96).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2387">19</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e2390">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Hyman LG, Lilienfeld AM, Ferris III FL, Fine SL . Senile macular degeneration: a case–control study. Am J Epidemiol 1983; 118: 213–227." href="/articles/6701978#ref-CR21" id="ref-link-section-d106275198e2393">21</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Eye Disease Case-Control Study Group. Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol 1992; 110: 1701–1708." href="/articles/6701978#ref-CR22" id="ref-link-section-d106275198e2396">22</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Age-related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case–control study in the age-related eye disease study: AREDS Report Number 3. Ophthalmology 2000; 107: 2224–2232." href="/articles/6701978#ref-CR24" id="ref-link-section-d106275198e2399">24</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y . Smoking and neovascular form of age related macular degeneration in late middle aged males: findings from a case–control study in Japan. Research Committee on Chorioretinal Degenerations. Br J Ophthalmol 1997; 81: 901–904." href="/articles/6701978#ref-CR25" id="ref-link-section-d106275198e2402">25</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Klein R, Klein BE, Linton KL, DeMets DL . The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol 1993; 137: 190–200." href="/articles/6701978#ref-CR28" id="ref-link-section-d106275198e2406">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Vingerling JR, Hofman A, Grobbee DE, de Jong PT . Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 1996; 114: 1193–1196." href="/articles/6701978#ref-CR29" id="ref-link-section-d106275198e2409">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e2412">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L . Smoking and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Arch Ophthalmol 1998; 116: 1031–1035." href="/articles/6701978#ref-CR31" id="ref-link-section-d106275198e2415">31</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR . Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol 2001; 119: 1455–1462." href="/articles/6701978#ref-CR32" id="ref-link-section-d106275198e2418">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e2421">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Vinding T, Appleyard M, Nyboe J, Jensen G . Risk factor analysis for atrophic and exudative age-related macular degeneration. An epidemiological study of 1000 aged individuals. Acta Ophthalmologica 1992; 70: 66–72." href="/articles/6701978#ref-CR34" id="ref-link-section-d106275198e2425">34</a></sup> A significant positive association between smoking and the risk of developing AMD was observed in six out of seven cross-sectional studies (RR/OR 1.30–4.96), three out of four cohort studies (OR/RR 1.70–3.70), and four out of six case–control studies (OR/RR 1.25–2.97).</p><p>In total, 10 studies evaluated ‘all AMD’ or ‘all late AMD’ and smoking; six studies found an association<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2432">19</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e2435">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e2438">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L . Smoking and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Arch Ophthalmol 1998; 116: 1031–1035." href="/articles/6701978#ref-CR31" id="ref-link-section-d106275198e2441">31</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR . Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol 2001; 119: 1455–1462." href="/articles/6701978#ref-CR32" id="ref-link-section-d106275198e2444">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Vinding T, Appleyard M, Nyboe J, Jensen G . Risk factor analysis for atrophic and exudative age-related macular degeneration. An epidemiological study of 1000 aged individuals. Acta Ophthalmologica 1992; 70: 66–72." href="/articles/6701978#ref-CR34" id="ref-link-section-d106275198e2447">34</a></sup> and two studies did not find an association.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989; 107: 875–879." href="/articles/6701978#ref-CR18" id="ref-link-section-d106275198e2451">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D et al. Case–control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol 1998; 82: 996–1002." href="/articles/6701978#ref-CR23" id="ref-link-section-d106275198e2454">23</a></sup> Hyman <i>et al</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Hyman LG, Lilienfeld AM, Ferris III FL, Fine SL . Senile macular degeneration: a case–control study. Am J Epidemiol 1983; 118: 213–227." href="/articles/6701978#ref-CR21" id="ref-link-section-d106275198e2460">21</a></sup> found an association in men only and Christen <i>et al</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2466">19</a></sup> found an association only at high intensities of smoking. In total, 10 studies evaluated neovascular AMD and six of these found a positive association;<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Eye Disease Case-Control Study Group. Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol 1992; 110: 1701–1708." href="/articles/6701978#ref-CR22" id="ref-link-section-d106275198e2471">22</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Age-related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case–control study in the age-related eye disease study: AREDS Report Number 3. Ophthalmology 2000; 107: 2224–2232." href="/articles/6701978#ref-CR24" id="ref-link-section-d106275198e2474">24</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y . Smoking and neovascular form of age related macular degeneration in late middle aged males: findings from a case–control study in Japan. Research Committee on Chorioretinal Degenerations. Br J Ophthalmol 1997; 81: 901–904." href="/articles/6701978#ref-CR25" id="ref-link-section-d106275198e2477">25</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Klein R, Klein BE, Linton KL, DeMets DL . The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol 1993; 137: 190–200." href="/articles/6701978#ref-CR28" id="ref-link-section-d106275198e2480">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Vingerling JR, Hofman A, Grobbee DE, de Jong PT . Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 1996; 114: 1193–1196." href="/articles/6701978#ref-CR29" id="ref-link-section-d106275198e2483">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e2486">30</a></sup> five studies evaluated atrophic AMD and four found a positive association.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Age-related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case–control study in the age-related eye disease study: AREDS Report Number 3. Ophthalmology 2000; 107: 2224–2232." href="/articles/6701978#ref-CR24" id="ref-link-section-d106275198e2490">24</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e2493">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e2496">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Vinding T, Appleyard M, Nyboe J, Jensen G . Risk factor analysis for atrophic and exudative age-related macular degeneration. An epidemiological study of 1000 aged individuals. Acta Ophthalmologica 1992; 70: 66–72." href="/articles/6701978#ref-CR34" id="ref-link-section-d106275198e2499">34</a></sup> In addition, some studies found the association was different for men or women. These variations could have been caused by random fluctuation because of relatively small numbers after stratifying by lesion type.</p><p>The results were not completely consistent and five studies found no association or only a very weak link between smoking and AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989; 107: 875–879." href="/articles/6701978#ref-CR18" id="ref-link-section-d106275198e2506">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D et al. Case–control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol 1998; 82: 996–1002." href="/articles/6701978#ref-CR23" id="ref-link-section-d106275198e2509">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Blumenkranz MS, Russell SR, Robey MG, Kott-Blumenkranz R, Penneys N . Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology 1986; 93: 552–558." href="/articles/6701978#ref-CR35" id="ref-link-section-d106275198e2512">35</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e2515">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e2518">37</a></sup> Of these, West <i>et al</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989; 107: 875–879." href="/articles/6701978#ref-CR18" id="ref-link-section-d106275198e2524">18</a></sup> found a nonsignificant decreased risk of AMD in ever-smokers in a small cross-sectional study, and Blumenkranz <i>et al</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Blumenkranz MS, Russell SR, Robey MG, Kott-Blumenkranz R, Penneys N . Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology 1986; 93: 552–558." href="/articles/6701978#ref-CR35" id="ref-link-section-d106275198e2530">35</a></sup> found a small nonsignificant increase among current-smokers in a small case–control study. More importantly, a generally well-conducted large French case–control study found only a weak and nonsignificant association between previous and current smoking with AMD after adjustment for confounding factors.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D et al. Case–control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol 1998; 82: 996–1002." href="/articles/6701978#ref-CR23" id="ref-link-section-d106275198e2534">23</a></sup> Finally, although the Beaver Dam Eye Study found a strong association between smoking and neovascular AMD at baseline,<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Klein R, Klein BE, Linton KL, DeMets DL . The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol 1993; 137: 190–200." href="/articles/6701978#ref-CR28" id="ref-link-section-d106275198e2539">28</a></sup> the association at the 5- and 10-year follow-up examinations was weaker.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e2543">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e2546">37</a></sup></p><p>Findings from the three large well-executed cross-sectional studies from Europe, Australia, and the USA demonstrate a consistent association between smoking and AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Klein R, Klein BE, Linton KL, DeMets DL . The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol 1993; 137: 190–200." href="/articles/6701978#ref-CR28" id="ref-link-section-d106275198e2552">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Vingerling JR, Hofman A, Grobbee DE, de Jong PT . Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 1996; 114: 1193–1196." href="/articles/6701978#ref-CR29" id="ref-link-section-d106275198e2555">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e2558">30</a></sup> The populations from these three key studies were combined giving a pooled population of 12 468 subjects.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001; 108: 697–704." href="/articles/6701978#ref-CR26" id="ref-link-section-d106275198e2562">26</a></sup> Apart from age, smoking was the only factor that retained a clear (three-fold) association with AMD (<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/6701978#Tab4">Table 4</a>). The association with current smoking was stronger for neovascular AMD compared with atrophic AMD.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-4"><figure><figcaption class="c-article-table__figcaption"><b id="Tab4" data-test="table-caption">Table 4 Age-adjusted associations between smoking and AMD—pooled analysis of three studies (current-smokers <i>vs</i> never-smokers and ex-smokers <i>vs</i> never-smokers): odds ratios (95% CI)</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/6701978/tables/4" aria-label="Full size table 4"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec8">Is there a temporal relationship?</h4><p>The prospective cohort study design is best for demonstrating that smoking preceded the development of AMD. The three key cross-sectional studies (the Beaver Dam Eye Study, the Rotterdam Study, and the Blue Mountains Eye Study) were subsequently extended into longitudinal studies; two studies reported results from further analysis of smoking and the risk of AMD after 5<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e2823">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e2826">36</a></sup> and 10 years<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e2830">37</a></sup> follow-up. In the Blue Mountains Eye Study, the association between all ARM and atrophic AMD (but not neovascular AMD) was still present 5 years from baseline.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e2834">33</a></sup> A further pooled analysis of the 5-year results from these three studies found a continued three-fold association of current smoking with development of AMD (<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/6701978#Tab4">Table 4</a>).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Tomany SC, Wang JJ, van Leeuwen R, Klein R, Mitchell P, Vingerling JR et al. Risk factors for incident age-related macular degeneration. Pooled findings from 3 continents. Ophthalmology 2004; 111: 1280–1287." href="/articles/6701978#ref-CR27" id="ref-link-section-d106275198e2841">27</a></sup> The Physicians' Health Study<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2846">19</a></sup> and the Nurses' Health Study<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e2850">20</a></sup> also observed positive associations between smoking and AMD after 7 years of follow-up.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec9">Is there a dose–response effect?</h4><p>Eight studies investigated a dose–response by comparing different levels of smoking, classified using pack-years (<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/6701978#Tab5">Table 5</a>).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2865">19</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e2868">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y . Smoking and neovascular form of age related macular degeneration in late middle aged males: findings from a case–control study in Japan. Research Committee on Chorioretinal Degenerations. Br J Ophthalmol 1997; 81: 901–904." href="/articles/6701978#ref-CR25" id="ref-link-section-d106275198e2871">25</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Vingerling JR, Hofman A, Grobbee DE, de Jong PT . Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 1996; 114: 1193–1196." href="/articles/6701978#ref-CR29" id="ref-link-section-d106275198e2874">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L . Smoking and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Arch Ophthalmol 1998; 116: 1031–1035." href="/articles/6701978#ref-CR31" id="ref-link-section-d106275198e2877">31</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR . Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol 2001; 119: 1455–1462." href="/articles/6701978#ref-CR32" id="ref-link-section-d106275198e2880">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e2884">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e2887">37</a></sup> All except the 10-year follow-up of the Beaver Dam cohort study identified a dose–response effect. In the 5-year follow-up results from the Beaver Dam study, the relative risk of early ARM increased as the amount smoked (measured in cigarette pack-years) increased.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e2891">36</a></sup> However, there appeared to be a negative association between the incidence of late ARM and the amount smoked in the 10-year follow-up.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e2895">37</a></sup> In female current-smokers and ex-smokers, an increasing number of cigarettes smoked was associated with an increased risk of developing AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e2899">20</a></sup> In men, current smokers of <20 cigarettes per day had a smaller relative risk of AMD compared with subjects who smoked ≥20 cigarettes per day.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2904">19</a></sup> When the length and duration of smoking were combined as pack-years, compared with never-smokers, there was an increasing risk of AMD as the number of pack-years increased from 0.25 to >40 (<i>P</i> for trend <0.001).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e2911">19</a></sup></p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-5"><figure><figcaption class="c-article-table__figcaption"><b id="Tab5" data-test="table-caption">Table 5 Studies examining the association between smoking and AMD: dose–response</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/6701978/tables/5" aria-label="Full size table 5"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Only one study has examined the age at onset of AMD in relation to smoking.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e3478">33</a></sup> In the Blue Mountains Eye Study, participants who were current smokers at the baseline examination and were free of late AMD, developed disease signs around 10 years younger than nonsmokers (mean ages 67 and 77 years, respectively).</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec10">Reversibility—what is the effect of stopping smoking?</h4><p>In total, 11 studies examined the risk of AMD in ex-smokers;<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e3490">19</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e3493">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Eye Disease Case-Control Study Group. Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol 1992; 110: 1701–1708." href="/articles/6701978#ref-CR22" id="ref-link-section-d106275198e3496">22</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y . Smoking and neovascular form of age related macular degeneration in late middle aged males: findings from a case–control study in Japan. Research Committee on Chorioretinal Degenerations. Br J Ophthalmol 1997; 81: 901–904." href="/articles/6701978#ref-CR25" id="ref-link-section-d106275198e3499">25</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Vingerling JR, Hofman A, Grobbee DE, de Jong PT . Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 1996; 114: 1193–1196." href="/articles/6701978#ref-CR29" id="ref-link-section-d106275198e3502">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e3505">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L . Smoking and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Arch Ophthalmol 1998; 116: 1031–1035." href="/articles/6701978#ref-CR31" id="ref-link-section-d106275198e3509">31</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR . Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol 2001; 119: 1455–1462." href="/articles/6701978#ref-CR32" id="ref-link-section-d106275198e3512">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e3515">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e3518">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e3521">37</a></sup> ex-smokers still had an increased risk of developing AMD compared with never-smokers but it was considerably lower than in current-smokers (<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/6701978#Tab6">Table 6</a>). In the pooled analysis of the three large cross-sectional studies and their associated cohort studies, ex-smokers had an only slightly increased risk of AMD compared with never-smokers (<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/6701978#Tab4">Table 4</a>).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001; 108: 697–704." href="/articles/6701978#ref-CR26" id="ref-link-section-d106275198e3531">26</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Tomany SC, Wang JJ, van Leeuwen R, Klein R, Mitchell P, Vingerling JR et al. Risk factors for incident age-related macular degeneration. Pooled findings from 3 continents. Ophthalmology 2004; 111: 1280–1287." href="/articles/6701978#ref-CR27" id="ref-link-section-d106275198e3534">27</a></sup> Further, in the 5- and 10-year follow-up of the Beaver Dam Eye Study,<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e3538">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e3541">37</a></sup> and in the 5-year follow-up of the Blue Mountains Eye study,<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e3546">33</a></sup> ex-smokers had a similar risk of developing AMD as never-smokers.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-6"><figure><figcaption class="c-article-table__figcaption"><b id="Tab6" data-test="table-caption">Table 6 Studies examining the association between stopping smoking and AMD: ex-smokers <i>vs</i> never-smokers</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/6701978/tables/6" aria-label="Full size table 6"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>The risk of developing AMD was higher in ex-smokers who reported having smoked >25 cigarettes/day compared with <25 cigarettes/day.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e4013">20</a></sup> The Physician's Health Study evaluated the risk of AMD in ex-smokers taking into account their previous intensity of smoking and the time since smoking cessation (years).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e4017">19</a></sup> Subjects who had smoked ≥20 cigarettes/day still appeared to have an increased risk of AMD even when they had stopped smoking >20 years previously. Ex-smokers who had smoked <20 cigarettes/day, regardless of when they stopped smoking, had a similar risk of AMD compared with never-smokers. Similarly, in the POLA study, former smokers seemed to remain at high risk for AMD for up to 20 years after stopping smoking.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L . Smoking and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Arch Ophthalmol 1998; 116: 1031–1035." href="/articles/6701978#ref-CR31" id="ref-link-section-d106275198e4021">31</a></sup></p></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec11-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec11">Discussion</h2><div class="c-article-section__content" id="Sec11-content"><p>The evidence fulfils established causality criteria and strongly suggests an association between smoking and AMD. The association is mostly consistent across a range of populations studied using different study types by different investigators. Depending on the type of AMD, the risk of developing the disease for current-smokers is two- or three-times the risk for never-smokers. The pooled analysis found a greater than four-fold increased risk for neovascular AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001; 108: 697–704." href="/articles/6701978#ref-CR26" id="ref-link-section-d106275198e4034">26</a></sup> Long-term follow-up of subjects in longitudinal studies demonstrates that exposure to smoking precedes the development of AMD. A dose–response effect has been demonstrated: the risk of developing AMD increases as the intensity of smoking increases.</p><p>The three large cross-sectional studies and their related cohort studies and pooled analyses provide particularly important evidence because of their large number of subjects, and the strength and rigour of the study designs.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Klein R, Klein BE, Linton KL, DeMets DL . The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol 1993; 137: 190–200." href="/articles/6701978#ref-CR28" id="ref-link-section-d106275198e4041">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Vingerling JR, Hofman A, Grobbee DE, de Jong PT . Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 1996; 114: 1193–1196." href="/articles/6701978#ref-CR29" id="ref-link-section-d106275198e4044">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e4047">30</a></sup></p><p>There was evidence that ex-smokers had a lower risk of AMD, suggesting reversibility of effect. Further evidence of the reversibility of the risk on removing the exposure comes from the Macular Photocoagulation Study (MPS).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Maguire MG, Klein ML, Chamberlin JA . Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy. Macular Photocoagulation Study Group. Arch Ophthalmol 1986; 104: 503–512." href="/articles/6701978#ref-CR38" id="ref-link-section-d106275198e4053">38</a></sup> The MPS investigators noted a higher rate of choroidal neovascular membrane recurrence after laser photocoagulation in patients who continued smoking compared with nonsmokers (85 <i>vs</i> 50%, <i>P</i>=0.02) receiving similar laser treatment. It is uncertain whether this also occurs for PDT and other novel AMD treatments over longer follow-up periods. These data are needed and should be collected. The potential for reversibility is important especially if the risk falls substantially after smoking cessation, as suggested by the Blue Mountains and Beaver Dam studies and from the pooled analyses.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001; 108: 697–704." href="/articles/6701978#ref-CR26" id="ref-link-section-d106275198e4063">26</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Tomany SC, Wang JJ, van Leeuwen R, Klein R, Mitchell P, Vingerling JR et al. Risk factors for incident age-related macular degeneration. Pooled findings from 3 continents. Ophthalmology 2004; 111: 1280–1287." href="/articles/6701978#ref-CR27" id="ref-link-section-d106275198e4066">27</a></sup> This could be a very useful public health message, as smokers with AMD in one eye might reduce their risk of progression to blinding, late-stage second eye involvement if they were able to stop smoking.</p><p>Plausible biological mechanisms support the involvement of smoking in the aetiology of AMD. Although the pathogenesis of AMD and the mechanism of action of smoking on the eye are not fully understood, the risk of developing AMD is likely to involve more than one mechanism. First, AMD may reflect accumulated oxidative damage in the retina.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Beatty S, Hui-Hiang K, Henson D, Boulton M . The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2000; 45: 115–134." href="/articles/6701978#ref-CR39" id="ref-link-section-d106275198e4073">39</a></sup> Smoking may also reduce choroidal blood flow in the eye, and promote ischaemia, hypoxia, and micro-infarctions, all of which could increase the susceptibility of the macula to degenerative changes.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Solberg Y, Rosner M, Belkon M . The association between cigarette smoking and ocular diseases. Surv Ophthalmol 1998; 42: 535–547." href="/articles/6701978#ref-CR40" id="ref-link-section-d106275198e4077">40</a></sup> Decreased choriocapillaris blood flow is associated with AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Lutty G, Grunwald J, Majji AB, Uyama M, Yoneya S . Changes in choriocapillaris and retinal pigment epithelium in age-related macular degeneration. Mol Vis 2004; 5: 35." href="/articles/6701978#ref-CR41" id="ref-link-section-d106275198e4081">41</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Ciulla TA, Harris A, Kagemann L, Danis RP, Pratt LM, Chung HS . Choroidal perfusion perturbations in non-neovascular age related macular degeneration. Br J Ophthalmol 2002; 86: 209–213." href="/articles/6701978#ref-CR42" id="ref-link-section-d106275198e4084">42</a></sup> Nicotine administration appeared to increase severity of experimental choroidal neovascularization in a mouse model.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Suner IJ, Espinosa-Heidmann DG, Marin-Castano ME, Hernandez EP, Pereira-Simon S, Cousins SW . Nicotine increases size and severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 2004; 45: 311–317." href="/articles/6701978#ref-CR43" id="ref-link-section-d106275198e4088">43</a></sup> Smoking has also been shown to reduce macular pigment optical density, which reflects levels of the protective carotenoids, lutein, and zeaxanthin in the macular retina.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Hammond Jr BR, Wooten BR, Snodderly DM . Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration. Vis Res 1996; 36: 3003–3009." href="/articles/6701978#ref-CR44" id="ref-link-section-d106275198e4092">44</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Hammond Jr BR, Caruso-Avery M . Macular pigment optical density in a Southwestern sample. Invest Ophthalmol Vis Sci 2000; 41: 1492–1497." href="/articles/6701978#ref-CR45" id="ref-link-section-d106275198e4095">45</a></sup> Weeks <i>et al</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Weeks DE, Conley PY, Tsai H-J, Mah TS, Schmidt S, Postel EA et al. Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26 and 17q25 regions. Am J Hum Genet 2004; 75: 174–189." href="/articles/6701978#ref-CR46" id="ref-link-section-d106275198e4102">46</a></sup> hypothesised that the effect of smoking on the risk of developing ARM is accentuated by a gene in the 10q26 region of the genome.</p><p>Although our review provides strong evidence for an AMD link with active smoking, the evidence for passive smoking increasing AMD risk is sparse.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Klein R, Klein BE, Linton KL, DeMets DL . The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol 1993; 137: 190–200." href="/articles/6701978#ref-CR28" id="ref-link-section-d106275198e4110">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e4113">30</a></sup> More recent studies of passive smoking tend to use much more comprehensive assessments of exposure in the workplace, home, and other settings. The question of whether passive smoking might cause AMD should be addressed using these methodologies before being dismissed on currently available evidence.</p><p>The presence of confounding factors presents a problem for all observational studies. Age is an accepted major risk factor for AMD and 15 studies adjusted results to account for age or age plus sex.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989; 107: 875–879." href="/articles/6701978#ref-CR18" id="ref-link-section-d106275198e4120">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE . A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996; 276: 1147–1151." href="/articles/6701978#ref-CR19" id="ref-link-section-d106275198e4123">19</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Seddon JM, Willett WC, Speizer FE, Hankinson SE . A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996; 276: 1141–1146." href="/articles/6701978#ref-CR20" id="ref-link-section-d106275198e4126">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Eye Disease Case-Control Study Group. Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol 1992; 110: 1701–1708." href="/articles/6701978#ref-CR22" id="ref-link-section-d106275198e4129">22</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D et al. Case–control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol 1998; 82: 996–1002." href="/articles/6701978#ref-CR23" id="ref-link-section-d106275198e4132">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Age-related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case–control study in the age-related eye disease study: AREDS Report Number 3. Ophthalmology 2000; 107: 2224–2232." href="/articles/6701978#ref-CR24" id="ref-link-section-d106275198e4135">24</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Tamakoshi A, Yuzawa M, Matsui M, Uyama M, Fujiwara NK, Ohno Y . Smoking and neovascular form of age related macular degeneration in late middle aged males: findings from a case–control study in Japan. Research Committee on Chorioretinal Degenerations. Br J Ophthalmol 1997; 81: 901–904." href="/articles/6701978#ref-CR25" id="ref-link-section-d106275198e4139">25</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Klein R, Klein BE, Linton KL, DeMets DL . The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol 1993; 137: 190–200." href="/articles/6701978#ref-CR28" id="ref-link-section-d106275198e4142">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Vingerling JR, Hofman A, Grobbee DE, de Jong PT . Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 1996; 114: 1193–1196." href="/articles/6701978#ref-CR29" id="ref-link-section-d106275198e4145">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Smith W, Mitchell P, Leeder SR . Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1518–1523." href="/articles/6701978#ref-CR30" id="ref-link-section-d106275198e4148">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L . Smoking and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Arch Ophthalmol 1998; 116: 1031–1035." href="/articles/6701978#ref-CR31" id="ref-link-section-d106275198e4151">31</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR . Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol 2001; 119: 1455–1462." href="/articles/6701978#ref-CR32" id="ref-link-section-d106275198e4154">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e4158">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e4161">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e4164">37</a></sup> Smoking is known to be associated with other health risk behaviours such as poor diet and excessive alcohol consumption.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Department of Health. Survey for England 1998: Cardiovascular Disease. Department of Health: London, 1999." href="/articles/6701978#ref-CR47" id="ref-link-section-d106275198e4168">47</a></sup> Poor diet is suspected of being a risk factor for AMD and hence is a potential confounding factor. However, only the Beaver Dam Eye Study, for the 5- and 10-year follow-up results adjusted for vitamin and alcohol intake.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e4172">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e4175">37</a></sup></p><p>Reviewing the data was complicated by variation in the definitions of exposure and outcome. There was no standard definition of the smoking and non-smoking status of subjects. All studies used subject-reported smoking data and it is possible that subjects underestimated or overestimated the extent of their smoking. Although all studies used the presence of AMD as an outcome measure, this is not a homogeneous diagnosis and definitions of disease (eg, differentiation of early and late AMD) varied between studies.</p><p>Five studies identified no association or only a weak association of AMD with smoking.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989; 107: 875–879." href="/articles/6701978#ref-CR18" id="ref-link-section-d106275198e4184">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D et al. Case–control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol 1998; 82: 996–1002." href="/articles/6701978#ref-CR23" id="ref-link-section-d106275198e4187">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Blumenkranz MS, Russell SR, Robey MG, Kott-Blumenkranz R, Penneys N . Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology 1986; 93: 552–558." href="/articles/6701978#ref-CR35" id="ref-link-section-d106275198e4190">35</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e4193">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e4196">37</a></sup> Two of these studies included relatively small numbers of subjects and did not define clearly the exposure and outcome.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol 1989; 107: 875–879." href="/articles/6701978#ref-CR18" id="ref-link-section-d106275198e4200">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Blumenkranz MS, Russell SR, Robey MG, Kott-Blumenkranz R, Penneys N . Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology 1986; 93: 552–558." href="/articles/6701978#ref-CR35" id="ref-link-section-d106275198e4203">35</a></sup> The large, French, multicentre private practice clinic-based, case–control study found a very weak and nonsignificant association between current or past smoking and AMD.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D et al. Case–control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol 1998; 82: 996–1002." href="/articles/6701978#ref-CR23" id="ref-link-section-d106275198e4207">23</a></sup> However, this study was atypical in that its setting was private eye clinics and subjects had a very low smoking prevalence. It is possible that under-reporting of smoking occurred or that ‘non-smokers’ may have included patients who had recently stopped smoking. If this under-reporting occurred differentially among the AMD patients, the estimated effect of smoking could have biased the results towards no effect. In addition, selection bias was a strong possibility as controls were eye clinic patients, most of whom had vascular eye diseases, which may also have been related to smoking. Finally, given the large number of studies included in the review, at least one study would be expected to have a null finding by chance alone.</p><p>The 5- and 10-year follow-up analyses of the Beaver Dam, Eye Study<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e4214">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598." href="/articles/6701978#ref-CR37" id="ref-link-section-d106275198e4217">37</a></sup> found none or a weak association of smoking with AMD in contrast with the cross-sectional baseline analysis.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Klein R, Klein BE, Linton KL, DeMets DL . The Beaver Dam Eye Study: the relation of age-related maculopathy to smoking. Am J Epidemiol 1993; 137: 190–200." href="/articles/6701978#ref-CR28" id="ref-link-section-d106275198e4221">28</a></sup> This may be partly because of small numbers of cases—only 56% of original subjects examined at baseline were evaluated during the 10-year follow-up. Dropout in cohort studies might also cause bias towards the null or even finding a protective effect of smoking if dropout occurred more frequently among smokers at highest risk of developing AMD or occurred more frequently among AMD patients who are smokers. This could theoretically happen in any of the cohort studies, particularly those with longer follow-up periods. This might result in bias if the smokers at highest risk of developing AMD were also those at highest risk of dropout because of serious ill health or death (eg, the heaviest smokers and smokers with multiple risk factors for coronary heart and neoplastic disease). This would result in the selective loss to the study of smokers at highest risk of AMD, leading to a reduction in the observed association between AMD and smoking. Whether differential loss to follow-up because of death or illness is a cause of bias is not clear. However, it is highly plausible as there is a mass of evidence from prospective studies that smokers have greatly increased mortality and morbidity, and this is greatest in heavy and prolonged smokers. The effect of such a bias is likely to increase with prolonged follow-up. The Beaver Dam Eye Study investigators did not find that AMD was associated with increased mortality in the analysis at 5 years.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Klein R, Klein BE, Moss SE . Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol 1998; 147: 103–110." href="/articles/6701978#ref-CR36" id="ref-link-section-d106275198e4225">36</a></sup> However, this contrasts with the findings of increased mortality among patients with AMD in the 10-year follow-up of the Rotterdam Study<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Borger PH, van Leeuwen R, Hulsman CA, Wolfs RC, van der Kuip DA, Hofman A et al. Is there a direct association between age-related eye diseases and mortality? The Rotterdam Study. Ophthalmology 2003; 110: 1292–1296." href="/articles/6701978#ref-CR48" id="ref-link-section-d106275198e4229">48</a></sup> and 6.5-year follow-up in the AREDS.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 49" title="Age-Related Eye Disease Study Research Group. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study: AREDS Report Number 13. Arch Ophthalmol 2004; 122: 716–734." href="/articles/6701978#ref-CR49" id="ref-link-section-d106275198e4233">49</a></sup></p><p>Finally, in the Blue Mountains Eye Study, current-smokers at the baseline examination who were still alive at follow-up were less likely to re-participate at 5 years.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Mitchell P, Wang JJ, Smith W, Leeder SR . Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 2002; 120: 1357–1363." href="/articles/6701978#ref-CR33" id="ref-link-section-d106275198e4239">33</a></sup> Lower participation rates among current-smokers compared with nonsmokers is well described in epidemiological studies. This would also be likely to result in an under-estimation of the strength of any smoking–AMD association if, as seems plausible, smokers at highest risk of AMD (ie, heavier smokers) were selectively dropping out in these studies.</p><p>A further potential bias in longitudinal studies examining disease associations with smoking is that nondifferential misclassification of exposure status may occur where smokers and nonsmokers are categorised at baseline only. This will not allow for the effect of changed exposure status, such as quitting smoking during follow-up. Such changes in exposure status are especially problematic with prolonged follow-up, and will bias the measure of association towards a null finding. An example of this problem comes from a recent negative study of the effects of passive smoking, which classified exposure largely by spousal smoking at baseline and attracted considerable critical comment as a result.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Enstrom KE, Kabat GC . Environmental tobacco smoke and tobacco related mortality in a prospective study of Californians, 1960–98. Br Med J 2003; 326: 1057–1067." href="/articles/6701978#ref-CR50" id="ref-link-section-d106275198e4247">50</a></sup></p></div></div></section><section data-title="Conclusion and relevance for practice"><div class="c-article-section" id="Sec12-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec12">Conclusion and relevance for practice</h2><div class="c-article-section__content" id="Sec12-content"><p>The epidemiological evidence strongly suggests a causal association between smoking and the development of AMD. In the UK, using population attributable risk calculations, we previously estimated that 53 900 cases of AMD (approximately one-quarter of all UK AMD cases) and 17 800 cases of AMD-related blindness may be attributable to cigarette smoking in people aged over 69 years.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Kelly SP, Thornton J, Lyratzopoulos G, Edwards R, Mitchell P . Smoking and blindness. Strong evidence for the link, but public awareness lags. Br Med J 2004; 328: 357–358." href="/articles/6701978#ref-CR51" id="ref-link-section-d106275198e4258">51</a></sup> Most cases of AMD remain irreversible and largely medically untreatable despite the emergence of new technologies.</p><p>The current review is the most comprehensive of the causal association between smoking and AMD to date. However, this review still has a number of limitations. Only a limited set of bibliographic databases were searched, non-English language articles were not included, there was no systematic appraisal of the quality of included studies, and a quantitative summary of the studies was not attempted. We next intend to address these deficiencies by carrying out a formal systematic review of smoking and a range of eye diseases including AMD.</p><p>Both the general population and many patients attending eye clinics are unaware of the strong link between smoking and eye disease. Anecdotal reports suggest that, when warned of the risk, most patients are keen and willing to stop smoking. The fear of going blind may be more motivational than warnings about other tobacco-associated disease. The additional ocular as well as systemic hazards of smoking should be highlighted to the public and patients.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Kelly SP, Thornton J, Lyratzopoulos G, Edwards R, Mitchell P . Smoking and blindness. Strong evidence for the link, but public awareness lags. Br Med J 2004; 328: 357–358." href="/articles/6701978#ref-CR51" id="ref-link-section-d106275198e4268">51</a></sup></p><p>Recognition of this association between smoking and eye disease has wider policy implications. The UK government is taking action to reduce smoking. The White Paper ‘Smoking Kills’ (<a href="http://www.dh.gov.uk/assetRoot/04/04/16/84/04041684.pdf">http://www.dh.gov.uk/assetRoot/04/04/16/84/04041684.pdf</a>) sets out a package of measures, including ending tobacco advertising and sponsorship, media campaigns aimed at changing attitudes towards smoking, and investment in smoking cessation initiatives. However, it is possible that those concerned with eye health are not giving enough weight to smoking cessation, and those concerned with tobacco control and smoking cessation are not giving enough emphasis to eye health.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Mitchell P, Chapman S, Smith W . ‘Smoking is a major cause of blindness’: a new cigarette pack warning? Med J Aust 1999; 171: 173–174." href="/articles/6701978#ref-CR52" id="ref-link-section-d106275198e4281">52</a></sup> We have made efforts to address this both in correspondence to UK authorities and in efforts at raising awareness through publication<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Kelly SP, Thornton J, Lyratzopoulos G, Edwards R, Mitchell P . Smoking and blindness. Strong evidence for the link, but public awareness lags. Br Med J 2004; 328: 357–358." href="/articles/6701978#ref-CR51" id="ref-link-section-d106275198e4285">51</a></sup> and in the production of a leaflet aimed at alerting eye clinic patients to the risks of smoking and helping them to quit (<a href="http://www.nwash.co.uk">www.nwash.co.uk</a>). In Australia, efforts on television and in other media to raise the public awareness of smoking as a cause of eye disease and blindness have been encouraging.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Carroll T, Rock B . Generating Quitline calls during Australia's National Tobacco Campaign: effects of television advertisement execution and programme placement. Tob Control 2003; 12 (Suppl 2): 40–44." href="/articles/6701978#ref-CR53" id="ref-link-section-d106275198e4296">53</a></sup> In New Zealand, media publicity about smoking and blindness resulted in increased telephone calls to the national Quitline<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Wilson N, Hodgen E, Mills J, Wilson G, Field A, Thomson G . Journal article on smoking and blindness prompts significantly more calls to Quitline. NZ Med J 2002; 115: 199–200." href="/articles/6701978#ref-CR54" id="ref-link-section-d106275198e4301">54</a></sup> and a campaign using the Australian eye television commercial (with minor modifications) was considered to have been more successful than other advertisements relating smoking to stroke and heart disease.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Wilson N, Grigg M, Cameron G, Afzal R, Glasgow H . Smoking and blindness advertisements are effective in stimulating calls to a national Quitline. Br Med J 2004; Rapid Response 18 March 
 http://bmj.bmjjournals.com/cgi/eletters/328/7439/537#53809
 
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Smoking and blindness advertisements are effective in stimulating calls to a national Quitline. <i>Br Med J</i> 2004; Rapid Response 18 March <a href="http://bmj.bmjjournals.com/cgi/eletters/328/7439/537%2353809" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="http://bmj.bmjjournals.com/cgi/eletters/328/7439/537%2353809">http://bmj.bmjjournals.com/cgi/eletters/328/7439/537#53809</a>.</p></li></ol><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/sj.eye.6701978?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>RE is unpaid chairman of NorthWest Action on Smoking and Health. This work was supported, in part, by endowment funds at Bolton Eye Unit Bolton Hospitals NHS Trust.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Division of Epidemiology and Health Sciences, Evidence for Population Health Unit, University of Manchester, Manchester, UK</p><p class="c-article-author-affiliation__authors-list">J Thornton, R Edwards & I Buchan</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">University of Sydney Department of Ophthalmology, Centre for Vision Research, Westmead Hospital, Westmead, Australia</p><p class="c-article-author-affiliation__authors-list">P Mitchell</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Bolton Primary Care Trust, St Peter's House, Bolton, UK</p><p class="c-article-author-affiliation__authors-list">R A Harrison</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Bolton Eye Unit. 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Mitchell, P. <i>et al.</i> Smoking and age-related macular degeneration: a review of association. <i>Eye</i> <b>19</b>, 935–944 (2005). https://doi.org/10.1038/sj.eye.6701978</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/sj.eye.6701978?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2004-12-18">18 December 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